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DOI: 10.1055/sos-SD-020-01227

Vanderwal, C. D.; Jacobsen, E. N.Science of Synthesis, (2007201322.

The use of phosphonate-stabilized carbanions to generate alk-2-enoic acid esters from aldehydes or ketones has seen extensive use in synthesis.[‌59‌] Advantages of this method include the ready accessibility of the required phosphonates, either from commercial ­sources or by the Arbuzov reaction of α-halo esters, the water solubility of the reaction byproducts, and the availability of protocols for the selective generation of either geometrical isomer in many synthetic contexts. The most common conversion of an aldehyde into an E-alk-2-enoic acid ester is exemplified by the homologation of aldehyde 98 into ester 100 using phosphonate 99 (Scheme 19).[‌60‌] An important modification of the HornerWadsworthEmmons reaction makes use of the combination of a Lewis acid and an amine base to generate the phosphonate-stabilized carbanion under mildly basic conditions; this allows for the use of both carbonyl substrates and phosphonate nucleophiles that bear base-sensitive groups. For example, aldehyde 101 is subject to base-mediated epimerization under standard alkenation conditions with phosphonate 102; however, with the use of a combination of lithium chloride and N,N-diisopropylethylamine, alk-2-enoic acid ester 103 is formed in high yield.[‌61‌] The control of alkene geometry is of high importance in these reactions, and thus reagents that selectively form the thermodynamically less stable Z-isomer have proven very useful. The use of the bis(trifluoroethyl)phosphonate ester 105 constitutes a great advance in the selective formation of Z-alk-2-enoic acid esters,[‌62‌] as exemplified by the conversion of dienal 104 into isomerically pure ester 106.[‌63‌] Another important method for the selective generation of Z-products makes use of diarylphosphonoacetic acid esters.[‌64‌‌66‌] The use of standard HornerWadsworthEmmons procedures in intramolecular contexts can be used to generate cyclic alk-2-enoic acid esters, as in the cyclization of 107 to macrocycle 108.[‌67‌] Ketones can also be alkenated, albeit with higher temperature demands (e.g., the reaction of 109 to 110).[‌68‌]

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